Virtual Screening, Molecular Docking, and Molecular Dynamics Simulation Studies on Potential Phytochemicals as Sphingosine Kinase 1 Inhibitors for Cancer Therapy

Abstract

Sphingosine kinases (SphKs) as lipid kinases catalyze the phosphorylation of sphingosine (Sph) to sphingosine-1-phosphate (S1P). Targeting the S1P signaling pathway is a significant strategy for many human diseases. Herein, we evaluated main prenylated bioactive components of a medicinal plant and performed a virtual screening study with flavonoid compounds and then, molecular docking and molecular dynamics (MD) simulation for the targeted cancer therapy. In silico ADMET and drug-likeness results were determined by BIOVIA Discovery Studio (DS). Molecular docking and molecular dynamics (MD) simulations were carried out by using Glide/SP and Desmond of Maestro with the filtered ligands. Glide/SP docking results showed higher binding affinity with xanthohumol (XN), 8-prenylnaringenin (8-PN), and neobavaisoflavone against SphK1. Three hits displayed strong hydrogen binding between the specific amino acid residues of targeting SphK1. There were no significant structural changes between SphK1-XN and SphK1-neobavaisoflavone complexes during 200 ns MD simulation analysis performed by GROMACS. Root-mean square deviation (RMSD) average values of XN- and neobavaisoflavone-protein complexes were compared to free SphK1 and were found as 0.2626 nm, 0.2589 nm, and 0.2508 nm, respectively. As a result, XN and 8-PN, and neobavaisoflavone have been determined as potential inhibitor candidates of SphK1 to examine for further in vitro and in vivo studies.

Keywords

• Sphingosine Kinase
• Virtual Screening
• Cancer
• Molecular Docking
• MD Simulation

Supporting Institution

Çanakkale Onsekiz Mart University, the Scientific Research Coordination Unit

Project Number

TSA-2021-3729

Thanks

This study was supported by Çanakkale Onsekiz Mart University, the Scientific Research Coordination Unit (Project number TSA-2021-3729). The website biorender.com was utilized for creating the workflow.

Kanser Tedavisinde Sfingozin Kinaz 1 İnhibitörleri Olarak Potansiyel Fitokimyasallar Üzerine Sanal Tarama, Moleküler Yerleştirme ve Moleküler Dinamik Simülasyon Çalışmaları

Abstract

Lipid kinazlar olarak sfingozin kinazlar (SphK), sfingozinin (Sph) sfingozin-1-fosfata (S1P) fosforilasyonunu katalize eder. S1P sinyal yolunu hedeflemek birçok insan hastalığı için önemli bir stratejidir. Burada, tıbbi bir bitkinin ana prenillenmiş biyoaktif bileşenlerini değerlendirdik ve flavonoid bileşiklerle sanal bir tarama çalışması ve ardından hedefe yönelik kanser tedavisi için moleküler yerleştirme ve moleküler dinamik (MD) simülasyonu gerçekleştirdik. In silico ADMET ve ilaca benzerlik sonuçları BIOVIA Discovery Studio (DS) tarafından belirlendi. Moleküler yerleştirme ve moleküler dinamik (MD) simülasyonları, filtrelenmiş ligandlarla birlikte Glide/SP ve Maestro Desmond kullanılarak gerçekleştirildi. Glide/SP yerleştirme sonuçları, ksantohumol (XN), 8-prenilnaringenin (8-PN) ve neobavaizoflavon ile SphK1'e karşı daha yüksek bağlanma ilgisi gösterdi. SphK1'i hedefleyen spesifik amino asit kalıntıları arasında üç molekül güçlü hidrojen bağlanması gösterdi. GROMACS tarafından gerçekleştirilen 200 ns MD simülasyon analizi sırasında SphK1-XN ve SphK1-neobavaizoflavon kompleksleri arasında önemli yapısal değişiklikler görülmedi. XN- ve neobavaizoflavon-protein komplekslerinin ortalama kare sapma (RMSD) ortalama değerleri, serbest SphK1 ile karşılaştırıldığında sırasıyla 0,2626 nm, 0,2589 nm ve 0,2508 nm olarak bulundu. Sonuç olarak XN ve 8-PN ile neobavaizoflavon, daha ileri in vitro ve in vivo çalışmalar için incelenmek üzere SphK1'in potansiyel inhibitör adayları olarak belirlendi.

Keywords

• Sifingozin kinaz
• sanal tarama
• kanser
• molekűler yerleştirme
• MD simülasyon

Supporting Institution

Çanakkale Onsekiz Mart Üniversitesi Bilimsel Araştırma Koordinasyon Birimi

Project Number

TSA-2021-3729

Thanks

Bu çalışma Çanakkale Onsekiz Mart Üniversitesi Bilimsel Araştırma Koordinasyon Birimi (Proje numarası TSA-2021-3729) tarafından desteklenmiştir. İş akışının oluşturulması için biorender.com web sitesinden yararlanılmıştır.

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